title: Neurotoxic and neuroprotective metabolites of kynurenine in patients with renal cell carcinoma treated with interferon-alpha: course and relationship with psychiatric status.
abstract: OBJECTIVE
  Immunotherapy with interferon-alpha (IFN-alpha) is associated with psychiatric side-effects, including depression. One of the putative pathways underlying these psychiatric side-effects involves tryptophan (TRP) metabolism. Cytokines including IFN-alpha induce the enzyme indoleamine 2,3-dioxygenase (IDO), which converts TRP to kynurenine (KYN), leading to a shortage of serotonin (5-HT). In addition, the production of neurotoxic metabolites of KYN such as 3-hydroxykynurenine and quinolinic acid (QA) might increase and contribute to IFN-alpha-induced psychopathology. In contrast, other catabolites of KYN, such as kynurenic acid (KA), are thought to have neuroprotective properties.
  
  
  METHODS
  In a group of 24 patients treated with standard IFN-alpha for metastatic renal cell carcinoma (RCC), combined psychiatric and laboratory assessments were performed at baseline, 4 and 8 weeks, and at 6 months.
  
  
  RESULTS
  No psychopathology was observed, despite an increase in neurotoxic challenge as reflected in indices for the balance between neurotoxic and neuroprotective metabolites of KYN.
  
  
  CONCLUSIONS
  The present hypothesis that a shift in the balance between neurotoxic and neuroprotective metabolites of KYN underlies the neuropsychiatric side-effects of IFN-alpha-based immunotherapy, is neither supported nor rejected.
authors.affiliation: Department of Psychiatry, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. a.vangool@erasmusmc.nl
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Van Gool
authors.forename: Robert
authors.initials: R
authors.lastname: Verkerk
authors.forename: Durk
authors.initials: D
authors.lastname: Fekkes
authors.forename: Marjolein
authors.initials: M
authors.lastname: Bannink
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.forename: Wim H J
authors.initials: WH
authors.lastname: Kruit
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.forename: Simon
authors.initials: S
authors.lastname: Scharpé
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Gerrit
authors.initials: G
authors.lastname: Stoter
authors.forename: Michiel W
authors.initials: MW
authors.lastname: Hengeveld
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy*; D003865:Major Depressive Disorder / Q000097:blood / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000097:blood*; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000097:blood*; D009483:Neuropsychological Tests; D009498:Neurotoxins / Q000097:blood*; D017378:Quinolinic Acid / Q000097:blood*
chemical_list: D007155:Immunologic Factors; D016898:Interferon-alpha; D018696:Neuroprotective Agents; D009498:Neurotoxins; C005045:3-hydroxykynurenine; D007737:Kynurenine; D017378:Quinolinic Acid